Candida albicans is a yeast-like fungal pathogen and can cause life-threatening hematogenously disseminated candidiasis. The cell surface of C. albicans is enriched with manose oligosaccharides and polysaccharides known as mannan that plays an important role in Candida-human interactions. We have developed the first full length human IgG1 antimannan antibody, M1g1, and found it to be protective in a mouse model of hematogenously disseminated candidiasis. This study along with results from murine antimannan antibodies indicate a role for antimannan antibody in host resistance to candidiasis. Our long term goal is to develop protective human anti-Candida antibodies for prophylactic and therapeutic applications. Recent studies have demonstrated that M1g1 initiates deposition of opsonic C3 fragments on C. albicans through the classical pathway in an Fc-dependent manner or through the alternative pathway in a novel Fc- independent Fab-dependent manner. However, M1g4, an IgG4 variant of M1g1, activates the alternative pathway only. M1g1 or M1g4 alone promotes phagocytosis of yeast cells by human neutrophils. However, complement enhanced phagocytosis of M1g4-opsonized yeast cells, not M1g1-opsonized yeast. Additional studies revealed a protective role for M1g4 in resistance to disseminated candidiasis. These observations suggest that the interplay between complement fragments and antimannan IgG, when deposited on cells as opsonins for phagocytes, may be synergistic, antagonistic, or indifferent and thus may influence the protective efficacy of an antimannan antibody. This hypothesis will be examined using a complete set of human IgG subclass variants, M1g1, M1g2, M1g3, and M1g4, that contain the same Fab, M1, but differ in the Fc region and Fc-mediated effector functions. The specific aims are: 1) To analyze the influence of IgG subclass specificity on antimannan antibody-mediated phagocytosis and phagocytic killing of C. albicans, 2) To determine the ability of IgG subclass variants of human antimannan antibody to activate the murine complement system, 3) To assess the effect of complement on IgG subclass-mediated phagocytosis and phagocytic killing of C. albicans, 4) To determine the influence of the complement system on the protective efficacy of IgG subclass variants of antimannan antibody, and 5) To evaluate the relative contribution of complement and IgG as opsonins for phagocytosis with genetically altered M1 antibodies that differ in Fc- mediated effector functions. Results from this study will provide insights into the mechanisms of antimannan antibody-mediated resistance to hematogenously disseminated candidiasis. These insights are valuable to the development of human protective antimannan antibodies for immunoprophylactic and immunotherapeutic applications. PUBLIC HEALTH RELEVANCE: Candida albicans is a yeast-like fungal pathogen and is among the most common causes of infections in hospitalized patients. This project will study the protective mechanisms of human anti-Candida antibodies.